Phase III Clinical Trial on the Immunogenicity and Safety of PapilloGuard4®
Clinical study on the immunogenicity and safety of the quadrivalent human papillomavirus vaccine, PapilloGuard4® (manufactured by Nivad Pharmed Salamat), in comparison with the quadrivalent Gardasil® vaccine (reference product, Merck) based on the Geometric Mean Concentration (GMC) ratio in healthy female and male volunteers aged 15 to 25 years; a Phase III randomized, double-blind, parallel-group, active-controlled non-inferiority clinical trial.
Sample size
670 participants
Study duration
7 months from the enrollment of the last volunteer
Study site
Mehr Hospital
4Study objectives
To evaluate the non-inferiority of the quadrivalent PapilloGuard4® vaccine (manufactured by Nivad Pharmed Salamat) compared with the quadrivalent Gardasil® vaccine (reference product, Merck) in terms of immunogenicity (GMC ratio) and safety in study volunteers.
Key inclusion criteria
- Female and male participants aged 15 to 25 years
- In good general health (as determined by clinical examination and medical history)
- Signed informed consent form (by the participant or their legal guardian)
- No fever above 37.5°C and no acute infectious illness within 24 hours prior to vaccination
Key exclusion criteria
- History of prior vaccination against HPV
- History of severe allergic reaction to any vaccine (including swelling of the mouth or throat, dyspnea, hypotension, urticaria, or anaphylactic shock) requiring medical intervention
- Individuals with immune system disorders or immunodeficiency
- History of chronic diseases such as cancer, hepatic or renal disorders, chronic pulmonary disease, heart failure, thyroid disease, neurological disorders, diabetes, or autoimmune diseases
Study methodology
This study was a Phase III randomized, double-blind, active-controlled, parallel-group, non-inferiority clinical trial designed to evaluate the immunogenicity and safety of PapilloGuard4® (manufactured by Nivad Pharmed Salamat) compared with the quadrivalent reference vaccine Gardasil® (manufactured by Merck). The evaluation was based on the Geometric Mean Concentration (GMC) ratio in healthy male and female volunteers aged 15 to 25 years who met the inclusion criteria.
A total of 670 participants (335 in each arm) were enrolled in a 1:1 randomization ratio. After signing informed consent and providing a baseline blood sample (for laboratory tests and pre-vaccination antibody concentration), participants were randomly assigned to one of the two study groups. Randomization was stratified by sex.
Vaccinations were administered on Day 0, Month 2, and Month 6. To determine antibody concentration, blood samples were collected 30 days after the third dose.
For safety monitoring, all participants were observed for 30 minutes after each vaccination, and any adverse events were recorded. Follow-up calls were made on Days 1, 7, 14, and 28 after each dose to monitor and document post-vaccination adverse effects.
Intervention details
In this study, 670 participants were equally divided into two groups:
Group 1 (n = 335)
Received the PapilloGuard4® 4 vaccine, manufactured by Nivad Pharmed Salamat
Group 2 (n = 335)
Received the Gardasil® vaccine, manufactured by Merck
Both vaccines were supplied as prefilled syringes containing antigens of human papillomavirus (HPV) types 6, 11, 16, and 18. Each dose (0.5 mL) was administered intramuscularly into the deltoid muscle of the non-dominant arm.
The dosing schedule for both groups consisted of three injections at months 0, 2, and 6.
Outcomes
Primary outcome (Immunogenicity)
- Antibody concentration against HPV types 6, 11, 16, and 18, measured as Geometric Mean Concentration (GMC) at 7 months after the first vaccine dose.
Secondary outcomes
- Proportion of participants with seroconversion against HPV types 6, 11, 16, and 18 on Days 60, 180, and 210 after the first dose.
- Antibody concentration (GMC) against HPV types 6, 11, 16, and 18 at Days 60 and 180 after the first dose.
- Occurrence of any solicited or unsolicited adverse events after each vaccine dose.
- Occurrence of any serious adverse events (SAE) following any vaccination dose.
Summary of Results
Immunogenicity Results
According to the study findings, the immunogenicity of PapilloGuard4® was non-inferior to that of Gardasil® on Day 210 (one month after the third dose), based on antibody concentrations against all four HPV types. It is noteworthy that the Geometric Mean Concentration (GMC) values for all four HPV types were higher in the PapilloGuard4® group compared with the Gardasil® group on Day 210.
| HPV Type | Parameter | Gardasil® / PapilloGuard4® Group | 95% Confidence Interval |
|---|---|---|---|
| Type 6 | GMCR | 2.04 | (1.74 – 2.40) |
| Type 11 | GMCR | 11.45 | (9.06 – 14.48) |
| Type 16 | GMCR | 1.58 | (1.34 – 1.86) |
| Type 18 | GMCR | 1.98 | (1.69 – 2.33) |
GMCR results of the PapilloGuard4® group compared with the Gardasil® group against HPV types 6, 11, 16, and 18 on day 210 by study group.
*According to WHO guideline, to determine the non-inferiority of PapilloGuard4® to Gardasil®, the lower bound of the 95% confidence interval for GMCR must be greater than 0.67.
The seroconversion rate, based on the laboratory-defined cut-off, was significantly higher for PapilloGuard® compared with Gardasil® on Day 210 (one month after the third dose) for HPV types 6, 11, and 18.
| HPV Type | Parameter | PapilloGuard® Group (n, %) | Gardasil® Group (n, %) | P-value |
|---|---|---|---|---|
| Type 6 | Seroconversion (%) | 263 (100.00) | 252 (98.05) | 0.03 |
| Type 11 | Seroconversion (%) | 195 (98.48) | 170 (89.47) | <0.0001 |
| Type 16 | Seroconversion (%) | 196 (98.99) | 193 (97.97) | 0.69 |
| Type 18 | Seroconversion (%) | 219 (99.55) | 218 (93.97) | <0.0001 |
Results of seroconversion rates against HPV types 6, 11, 16, and 18 on day 210 by study group
Safety results
Overall, the most common adverse event in both groups was pain at the vaccination site, which was generally mild and transient. Among all reported systemic adverse events, headache and fatigue were the most frequently observed.
Comparative Table of PapilloGuard4® and Gardasil® Quadrivalent Vaccines
| Feature | Gardasil® (Merck, USA) | PapilloGuard4® (Nivad Pharmed Salamat, Iran) |
|---|---|---|
| Vaccine type | Quadrivalent HPV vaccine | Quadrivalent HPV vaccine |
| Covered HPV types | HPV 6, 11, 16, 18 | HPV 6, 11, 16, 18 |
| Adjuvant type | Amorphous aluminum hydroxyphosphate sulfate (AAHS) | AS04 containing aluminum hydroxide and MPL |
| Manufacturer | Merck, USA | Nivad Pharmed Salamat, Iran |
| Immune response (Immunogenicity) | For all four HPV types (6, 11, 16, 18), on Day 210, the Geometric Mean Concentration Ratio (GMCR) of PapilloGuard4® was non-inferior to Gardasil®, and the Geometric Mean Concentration (GMC) values were higher for PapilloGuard4®. | |
| Seroconversion | On Day 210 after the first dose, seroconversion rates for HPV 6, 11, and 18 were significantly higher in PapilloGuard4® compared with Gardasil®. | |
| Local adverse effects | Most common: pain at the injection site | |
| Systemic adverse effects | Most common: fatigue and headache; incidence comparable between groups | |
| Production status | Imported, higher cost | Locally manufactured, cost-effective, ensuring cold chain compliance |
